Life cycle of adult hippocampal newborn neuron uncovered

Unlocking the mystery of neurological disorders starts with understanding how neurons are generated and maintained. Recently, researchers at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Baylor College of Medicine discovered that the life cycle of adult hippocampal newborn neurons was not what was previously thought. Their studies opened new doorways for future research on the process by which neurons are generated.

The findings, which appear in the current issue of the journal Cell Stem Cell, show that very early after birth, within 1-4 days of life, newborn cells reach a critical stage when many of them die by apoptosis, natural cell death. In addition, the study revealed that those dead cells are cleared very rapidly, the two processes being intrinsically coupled.

"Years ago researchers believed we were born with only a certain number of neurons to last us throughout our lifetime, but we soon learned that new ones are also produced in adulthood. Our current research is focused on the life cycle of those neurons," said Amanda Sierra Saavedra, postdoctoral associate in pediatrics-neurology at NRI/BCM, from the laboratory of Dr. Mirjana Maletic-Savatic.

The area where these new neurons are produced is the hippocampus, a brain area responsible for learning and memory. Thus, the critical processes discovered by the reported study could potentially play a role in learning and memory and disorders that affect the hippocampus, Sierra Saavedra added.

She and the team of researchers under the leadership of Dr. Mirjana Maletic-Savatic, assistant professor of pediatrics-neurology at NRI/BCM, were able to label and follow each new neuron using BrdU (Bromodeoxyuridine). BrdU can be incorporated into the newly synthesized DNA of dividing cells. Thus, this technique enables researchers to follow the life cycle of a newborn cell.

"We found two critical periods when the newborn cells underwent apoptosis, and the majority of the cells died one to four days after being born," said Sierra Saavedra. "This is much earlier than what we had first thought. We were completely puzzled to learn that many cells die almost immediately after they are born."

As researchers followed these cells, they soon learned that the "clearing up", or phagocytosis, began immediately following cell death. Microglia cells, which make up the immune defense system of the brain, engulf the dead cells, destroying them and leaving behind little to no trace of them.

"This process happens quickly, efficiently, and without any interference, indicating that the microglia play an important role in maintaining the proper functions of the neurogenic process," Sierra Saavedra said. "If this is interrupted by genetic, environmental, toxic, or immunologic defaults or any other reason, then we believe that certain diseases and disorders might appear."

These findings provide very important steps necessary for the future investigations into novel ways of harnessing newborn neurons for treating disorders related to the hippocampus, she said.

This work was supported by the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Intellectual and Developmental Disabilities Research Center, and the Farish Foundation.

Others who contributed to this research include Juan M. Encinas, Department of Pediatrics at BCM and Cold Spring Harbor Laboratory; Juan J.P. Deudero, Department of Pediatrics at BCM; Jessica H. Chancey and Linda S. Overstreet-Wadiche, both with the Department of Neurobiology, University of Alabama; Grigori Enikolopov, Cold Spring Harbor Laboratory; and Stella E. Tsirka, Department of Pharmacology, Stony Brook University.